The importance of the bone marrow in hematopoiesis has been well documented. However, the function of bone marrow in tumor T cell immunity is not well understood. Regulatory T cells (Tregs), dendritic cells (DOs) and effector T cells are found in the bone marrow. In this proposal, we focus on the cross-talk between Tregs, DCs and bone cells in the context of tumor bone marrow metastasis. We hypothesize that tumor bone marrow environmental cells provide cellular and molecular signals for Treg expansion, and that Tregs contribute to bone immunopathology in tumor bone marrow metastasis. Receptor activator of NF-kB (RANK) and its ligand RANKL signals are implicated in Treg expansion in diabetes and ultraviolet-induced immune suppression. We hypothesize that DCs in the tumor associated bone marrow environment provide specific molecular signals for Treg expansion, and RANK/RANKL is the molecular pathway mediated Treg expansion. The numbers and function of osteoblast and osteoclast control the balance between bone deposition and resorption. We hypothesize that bone marrow Tregs promote bone deposition, the main bone pathology of prostate cancer bone metastasis, through inhibiting osteoclast differentiation and function, and tilting the balance toward osteoblasts. Our specific aims are: Aim 1: To test the hypothesis that Tregs expand in the tumor associated BM in mouse model Aim 2: To test the hypothesis that tumor associated BM DCs induce Treg expansion in mouse model